Compounds based on the ergoline ring system ##STR1## have a surprising variety of pharmaceutical activities. For example, lysergic and isolysergic acid are 8-carboxy-6-methyl-9-ergolenes. The amides of lysergic acid, many of which have valuable and unique pharmacologic properties, include the naturally occurring oxytocic alkaloids-ergocornine, ergokryptine, ergonovine, ergocristine, ergosine, ergotamine, etc. - and synthetic oxytocics such as methergine, as well as the synthetic hallucinogen - lysergic acid diethylamide or LSD. The corresponding amides of 6-methyl-8-carboxyergoline, known generically as dihydroergot alkaloids, are oxytocic agents of lower potency and also lower toxicity than the ergot alkaloids themselves. Recently, it has been found by Clemens, Semonsky, Meites and their various co-workers, that many ergot-related drugs have activity as prolactin inhibitors, including ergocornine, dihydroergocornine, 2-bromo-.alpha.-ergokryptine and d-6-methyl-8-cyanomethylergoline. References embodying some of these newer findings in this field of ergoline pharmacology are the following: Naqasawa and Meites, Proc. Soc. Exp't'l. Biol. Med, 135, 469 (1970); Lutterbeck et al., Brit. Med. J., 228, (July 24, 1971); Heuson et al., Europ. J. Cancer, 353 (1970); Coll. Czech, Chem. Commun., 33 577 ( 1968); Nature, 221, 666 (1969); Seda et al., J. Reprod. Fert., 24, 263 (1971); Mantle and Finn, id 441; Semonsky and co-workers, Coll. Czech. Chem. Comm, 36, 2200 (1971); Schaar and Clemens, Endocr., 90, 285-8 (1972); Clemens and Schaar, Proc. Soc. Exp. Biol. Med., 139 659-662-(1972) and Sweeney.Iadd., .Iaddend.Clemens, Kornfield and Poore, 64th Annual Meeting, American Association Cancer Research, April 1973. Recently issued patents in the field of ergoline derivatives or lysergic acid derivatives include but are not limited to the following: U.S. Pat. No. 3,704,233, U.S. Pat. No. 3,901,891, U.S. Pat. No. 3,709,891, U.S. Pat. No. 3,585,201, U.S. Pat. No. 3,666,762, U.S. Pat. No. 3,901,893, U.S. Pat. No. 3,752,814, U.S. Pat. No. 3,879,554, U.S. Pat. No. 3,586,683, U.S. Pat. No. 3,717,640, U.S. Pat. No. 3,592,816, U.S. Pat. No. 3,883,655, U.S. Pat. No. 3,901,894, U.S. Pat. No. 3,920,664, U.S. Pat. No. 3,901,894 and U.S. Pat. No. 3,922,347.
Only a few 8,8-disubstituted ergolines have been prepared. A majority of these compounds have also had substituent on the indole nitrogen thus yielding a 1,8,8-trisubstituted derivative. For example, Baker et al. publishing in Molecular Pharmacology, 9, 23 (1973) reported 1,8-dimethyl-D-lysergic acid p-bromanilide. This compound showed no hallucinogenic activity unlike D-lysergic acid p-bromanilide. The same compound is mentioned in Science, 178, 614 (1972). Troxler and Hofmann.Iadd., .Iaddend.Helvetica .[.Chemica.]. .Iadd.Chimica .Iaddend.Acta, 40, 1722 (1957) prepared a mixture of the 1,8-dimethyl and the 8-methyl derivatives of D-isolysergic acid diethylamide. The two products were separated by chromatography. The authors stated, however, that they were unable to obtain similar substitution products alkylated at C.sub.8 from dihydrolysergic acid methyl ester although they employed the alkylating mixture which had been used successfully with lysergic acid itself; to wit, 2 moles of methyliodide and 8 moles of potassium amide. These authors also prepared in similar fashion 8-ethyl-D-isolysergic acid diethylamide and the 1,8-dimethyl-D-isolysergic acid diethylamide as a mixture separable by chromatography.
There is no mention in the literature of an 8,8-disubstituted-9-ergolene in which the substituents at 8 are other than amide groups and in which the 1-position is not substituted. 6-Methyl-8,8-disubstituted ergolines are not mentioned in the literature.